Non-nucleotide composition for inhibiting platelet aggregation

Abstract

This invention is directed to a method of preventing or treating diseases or conditions associated with platelet aggregation. The method is also directed to a method of treating thrombosis or related disorders. The method comprises administering to a subject a pharmaceutical composition comprising an effective amount of a non-nucleotide compound, preferably a P2Y 12 receptor antagonist compound, wherein said amount is effective to inhibit platelet aggregation. The compounds useful for this invention include compounds of general Formulae I and III-XII, or salts, hydrates, and solvates thereof. The present invention also provides novel compounds of Formulae I and III-XII.

1. A compound of Formula V, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R a ═R c ═H;
 R b  is selected from the group consisting of: hydrogen, C 1-8  alkyl, C 1-8  alkenyl, C 1-8  alkynyl, C 3-7  cycloalkyl, C 4-7  cycloalkenyl, aralkyl, and aryl, where all rings or chains optionally bear one or more substituents; 
 R d  and R d′  are independently selected from the group consisting of: H, C 1-8  alkyl, C 1-8  alkenyl, C 1-8  alkynyl, and C 3-7  cycloalkyl; 
 R e  is absent; 
 R f  and R g  are independently selected from the group consisting of: —H, halogen, C 1-8  alkyl, C 1-8  alkenyl, C 1-8  alkynyl, and C 3-7  cycloalkyl; 
 R h  is H, alkyl, aryl, or aralkyl; 
 G is O; 
 J is carbon; 
 D is O; 
 X 1  is selected from the group consisting of: N and C-M; and 
 M is independently selected from the group consisting of: —H, halogen, —CF 3 , C 1-8  alkyl, cyano, C 1-8  alkenyl, C 1-8  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkenyl, aryl, aralkyl, heteroaryl, saturated or unsaturated C 2-6  heterocycle, —OH, saturated or unsaturated C 1-6  alkoxy, aralkoxy, aryloxy, —SH, C 1-6  thioalkyl, thioaryl, —[(CO)OR], —[(CO)NRR], amino, —N-substituted amino, and N,N-disubstituted amino; wherein each said substituent on said amino of M is independently selected from the group consisting of: C 1-8  alkyl, C 3-7  cycloalkyl, aryl, aralkyl, —[(CO)R], —[(CO)O—(C 1-8  alkyl)], and —[(CO)—NRR]; and when M is —[(CO)NRR], —[NH(CO)NRR], —[N(C 1-8  alkyl)(CO)NRR], —[N(aryl)(CO)NRR], or —[N(aralkyl)(CO)NRR], the R groups of any said —NRR unit in M are optionally taken together such that a ring of 3 to 7 members is formed, with or without heteroatoms in place of the ring-carbon units; 
 A 2  is CH 2 , where the hydrogen on C is optionally substituted with alkyl; or 
 A 2  is absent. 
 
     
     
       2. The compound according to  claim 1 , wherein M is —H, halogen, C 1-4 alkyl, C 1-4 alkoxy, CF 3 , cyano, or amino. 
     
     
       3. The compound according to  claim 2 , wherein M is —H. 
     
     
       4. The compound according to  claim 1 , wherein R d ′ is C 1-8 alkyl or C 3-7 cycloalkyl. 
     
     
       5. The compound according to  claim 1 , wherein R b  is aryl or aralkyl. 
     
     
       6. The compound according to  claim 5 , wherein said R b  is phenyl, benzyl, or styryl. 
     
     
       7. The compound according to  claim 1 , wherein A 2  is absent. 
     
     
       8. The compound according to  claim 1 , wherein said compound is selected from the group consisting of Compounds 154-162: